Zinc chelation inhibits HIV Vif activity and liberates antiviral function of the cytidine deaminase APOBEC3G

Zuoxiang Xiao; Elana Ehrlich; Kun Luo; Yong Xiong; Xiao Fang Yu

doi:10.1096/fj.06-6773com

Zinc chelation inhibits HIV Vif activity and liberates antiviral function of the cytidine deaminase APOBEC3G

Zuoxiang Xiao, Elana Ehrlich, Kun Luo, Yong Xiong, Xiao Fang Yu

Bloomberg School of Public Health

Research output: Contribution to journal › Article › peer-review

Abstract

APOBEC3 proteins are cellular antiviral proteins that are targeted for proteasomal degradation by primate lentiviral Vif proteins. Vif acts as a substrate receptor for the Cullin5 (Cul5) E3 ubiquitin ligase, specifically interacting with Cul5 through a novel H-_x5-C_-x17-18-C- _x3-5-H zinc binding motif. Using the membrane-permeable zinc chelator, N,N,N′,N′-tetrakis-(2-pyridylmethyl) ethylenediamine (TPEN), we demonstrated a requirement for zinc for Vif function in vivo. Treatment with TPEN at an IC50 of 1.79 μM inhibits Cul5 recruitment and APOBEC3G (A3G) degradation. Zinc chelation prevented Vif function in infectivity assays, allowing the virus to become sensitive to the antiviral activity of A3G. Zinc chelation had no effect on cellular Cul5-SOCS3 E3 ligase assembly, suggesting that zinc-dependent E3 ligase assembly may be unique to HIV-1 Vif, representing a new target for novel drug design.

Original language	English (US)
Pages (from-to)	217-222
Number of pages	6
Journal	FASEB Journal
Volume	21
Issue number	1
DOIs	https://doi.org/10.1096/fj.06-6773com
State	Published - Jan 1 2007

Keywords

HIV-1 virion
Lentiviral Vif proteins
TPEN
Zinc binding motif

ASJC Scopus subject areas

Biotechnology
Biochemistry
Molecular Biology
Genetics

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title = "Zinc chelation inhibits HIV Vif activity and liberates antiviral function of the cytidine deaminase APOBEC3G",

abstract = "APOBEC3 proteins are cellular antiviral proteins that are targeted for proteasomal degradation by primate lentiviral Vif proteins. Vif acts as a substrate receptor for the Cullin5 (Cul5) E3 ubiquitin ligase, specifically interacting with Cul5 through a novel H-x5-C-x17-18-C- x3-5-H zinc binding motif. Using the membrane-permeable zinc chelator, N,N,N′,N′-tetrakis-(2-pyridylmethyl) ethylenediamine (TPEN), we demonstrated a requirement for zinc for Vif function in vivo. Treatment with TPEN at an IC50 of 1.79 μM inhibits Cul5 recruitment and APOBEC3G (A3G) degradation. Zinc chelation prevented Vif function in infectivity assays, allowing the virus to become sensitive to the antiviral activity of A3G. Zinc chelation had no effect on cellular Cul5-SOCS3 E3 ligase assembly, suggesting that zinc-dependent E3 ligase assembly may be unique to HIV-1 Vif, representing a new target for novel drug design.",

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AU - Xiao, Zuoxiang

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AU - Xiong, Yong

AU - Yu, Xiao Fang

PY - 2007/1/1

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N2 - APOBEC3 proteins are cellular antiviral proteins that are targeted for proteasomal degradation by primate lentiviral Vif proteins. Vif acts as a substrate receptor for the Cullin5 (Cul5) E3 ubiquitin ligase, specifically interacting with Cul5 through a novel H-x5-C-x17-18-C- x3-5-H zinc binding motif. Using the membrane-permeable zinc chelator, N,N,N′,N′-tetrakis-(2-pyridylmethyl) ethylenediamine (TPEN), we demonstrated a requirement for zinc for Vif function in vivo. Treatment with TPEN at an IC50 of 1.79 μM inhibits Cul5 recruitment and APOBEC3G (A3G) degradation. Zinc chelation prevented Vif function in infectivity assays, allowing the virus to become sensitive to the antiviral activity of A3G. Zinc chelation had no effect on cellular Cul5-SOCS3 E3 ligase assembly, suggesting that zinc-dependent E3 ligase assembly may be unique to HIV-1 Vif, representing a new target for novel drug design.

AB - APOBEC3 proteins are cellular antiviral proteins that are targeted for proteasomal degradation by primate lentiviral Vif proteins. Vif acts as a substrate receptor for the Cullin5 (Cul5) E3 ubiquitin ligase, specifically interacting with Cul5 through a novel H-x5-C-x17-18-C- x3-5-H zinc binding motif. Using the membrane-permeable zinc chelator, N,N,N′,N′-tetrakis-(2-pyridylmethyl) ethylenediamine (TPEN), we demonstrated a requirement for zinc for Vif function in vivo. Treatment with TPEN at an IC50 of 1.79 μM inhibits Cul5 recruitment and APOBEC3G (A3G) degradation. Zinc chelation prevented Vif function in infectivity assays, allowing the virus to become sensitive to the antiviral activity of A3G. Zinc chelation had no effect on cellular Cul5-SOCS3 E3 ligase assembly, suggesting that zinc-dependent E3 ligase assembly may be unique to HIV-1 Vif, representing a new target for novel drug design.

KW - HIV-1 virion

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KW - Zinc binding motif

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Zinc chelation inhibits HIV Vif activity and liberates antiviral function of the cytidine deaminase APOBEC3G

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